We will continue studies of the nitrogen metabolism of nervous tissue, in the broadest sense, directing our efforts to specific problems related to the effects of naturally-occurring amino acids and related substances on neuronal excitability and synaptic transmission in health and disease. One of the concerns of the project is the role of the alpha-aminobutyric acid (GABA) system in central nervous system function. One objective is to develop suitable strategies for the devisal of pharmacologically active substances which will allow specific manipulation of various aspects of the GABA system in vivo eventually for use in neurological and psychiatric disorders. Such substances would presumably be specific GABA agonists or antagonists or substances that specifically could influence the synaptic inactivation of GABA by carrier-mediated transport. Another goal is to purify Drosophila glutamic decarboxylase and choline-acetyltransferase with the eventual aim of visualizing these enzymes by immunocytochemical methods in nervous systems of normal flies and in neurological mutants. This could give insights into normal and abnormal relations of neurons empolying known specific transmitters. We hope to develop a GABA macro-electrode (eventually a microelectrode) which would make possible easy determinations of GABA concentrations in solutions and tissue extracts, and eventually in single cells. We are attempting to establish an armamentarium of ultramicro analytical procedures (GC-MS methods) for the determination of a variety of imidazole compounds of natural occurrence in the nervous system and to use these methods for the study of metabolism of these little-studied substances and the resolution of the questions as to whether or not imidazol-4-acetic acid is a neurotransmitter in the vertebrate nervous system. Studies will be continued to determine at cell structural and molecular levels the defect in mice with hereditary spasticity.